Over the past decade, there has been rapid evolution and expansion in scientific and community interest in HIV curative strategies. The initial report of the cure of Timothy Brown (The Berlin Patient) following CCR5 Ī32/Ī32 stem-cell transplantation in 2009 [1] was a major catalyst in bringing together various stake-holders, including government funding agencies, private foundations, community and advocacy groups, ethicists, regulatory agencies, pharmaceutical companies, scientists and clinicians, to work towards the goal of achieving a sterilizing cure or durable control of HIV after stopping antiretroviral therapy (ART). Dedicated funding opportunities provided support for those working towards these challenging goals, leading to an exponential increase in the number of scientific articles, public articles and media coverage. The status of these efforts was extensively summarized by the International AIDS Society global strategy towards an HIV cure in 2016 [2]. Although additional cases such as Timothy Brown have yet to materialize, the HIV cure field has rapidly expanded to include work on discovering biomarkers of persistent HIV infection, development and implementation of immunological approaches to controlling HIV following ART cessation, cell and gene therapy approaches, early initiation of ART, latency promoting or reversing strategies and development of novel assays to locate, quantify and characterize persistent HIV reservoirs. Although working towards an HIV cure has been met with many scientific and practical challenges, there has been recent, palpable progress. For example, durable control of simian immunodeficiency virus (SIV) has recently been reported in nonhuman primate studies including the use of therapeutic HIV vaccine combined with Toll-like receptor agonists and mAbs directed towards viral envelope proteins or Ī±4Ī²7 integrin, to name just a few [3ā5]. Additional cases of prolonged HIV remission prior to viral recrudescence, sometimes lasting many months, have been reported in small, proof-of-concept human studies, although none have lead to unequivocal, sustained HIV cure [6,7]. Work on other strategies has also accelerated, including the search for biomarkers of residual HIV-infected cells or the development of clinical trials incorporating combination therapies to target or modulate various aspects of HIV persistence. Of course, there have been, and always will be, growing pains and false starts while embarking upon novel and innovative cure science, but there is no disputing that the past decade has seen a dramatic increase in the understanding of HIV persistence. However, there are several fundamental questions within HIV curative persistence research that remain unclear. Defining what is meant by an HIV ācureā has undergone several iterations with an emerging consensus that achieving control of HIV following cessation of ART will require immune control in addition to reservoir reduction. This is different from a āsterilizingā cure achieved with Timothy Brown, but nonetheless offers the hope of reducing or eliminating the need for life-long ART. Other questions remain. For example, how do we define HIV latency, and what specifically defines and makes up the viral reservoir? Are all infected cells that remain in the setting of āsuppressiveā ART important to identify and target, regardless of the degree of transcriptional or translational activity? What level of reservoir reduction will be required to allow immune or other control of HIV replication following treatment interruption? What is the total body distribution and activity of persistently infected cells? Regardless of these ongoing questions, a more robust framework now exists on which HIV eradication and control studies can be designed and evaluated. In several other infectious disease contexts, alternative therapeutic approaches are also urgently needed to circumvent failures or insufficiencies associated with existing antimicrobial agents [6,7]. Lessons for achieving an HIV cure must be drawn from the evolution of these therapeutic strategies and those developed in the fields of oncology and solid organ and stem cell transplantation. For example, immunosuppressive agents such as rapamycin may have unexpected positive impacts on tuberculosis (TB) or HIV infection, and other drugs that are already clinically approved and ready to enter clinical trials, such as metformin, may also have potential impact on TB infection. Immune checkpoint blockade is another example of an immune modifying therapy primarily developed for various cancers that may have some beneficial impact on HIV infection in certain individuals, but also carries significant potential risks. In this issue of Current Opinion in HIV and AIDS, experts in HIV persistence and eradication efforts cover recent findings in topics such as biomarkers of HIV reservoirs, genital reservoirs, posttreatment control of HIV infection, therapeutic vaccination, mathematical approaches to understanding persistence and viral eradication, immunomodulatory therapies for HIV, chimeric antigen receptor T-cell approaches and analytical treatment interruptions. Ethical and clinical issues of trials to achieve functional cure are also addressed which are critical to achieving a well tolerated and scalable HIV cure. In contrast to standard antiretrovirals, which are well tolerated, many HIV curative strategies are not devoid of potential deleterious effects. Moreover, treatment interruptions alone as a means of assessing the effectiveness of these strategies may also carry risks, including viral recrudescence and exposure to secondary transmission risks. The establishment of clinical cure trials leads to a paradigm shift in the management of HIV of which participants, clinicians and researchers must be aware. Clearly, the HIV curative field is much larger and more involved than what can be summarized in just a few articles, but the breadth and depth of the research presented attests to the importance and durability of searching for a cure. Although progress towards HIV cure has yet to achieve the number or breath of these successes, it is much easier to be an optimist in this exciting era of scientific and community research. However, momentum will only continue if there are continued interest and support from all parties involved. Acknowledgements None. Financial support and sponsorship T.J.H. is supported by NIH/NIAID R01AI122862 and R33AI116205. Conflicts of interest T.J.H. provides consulting services to Merck and receives grant support from Gilead Biosciences.
Ongoing scale-up of HIV programs in an era of leveling funds for health require that each dollar is spent efficiently and effectively. From 2004 to 2009, the number of people on antiretroviral treatment (ART) grew from 700 000 to 5.2 million, with a 30% increase realized in 2009 alone [1]. At the same time, for every person starting therapy two others get infected, and the unmet need continues to grow. At the end of 2009, there were 9 million HIV-infected people who were eligible for ART but had not yet started treatment [2]. The Joint United Program on HIV/AIDS (UNAIDS) estimates that in 2009 US$ 15.9 billion was available for HIV/AIDS control globally, US$ 10 billion short of what was needed. There is also a recognized need to re-prioritize other areas of health, notably maternal and child care [3] and to reach universal health coverage [4]. Medium and long-term solutions require significant investment in health systems, increasing the money for health and maximizing health outcomes from available money [4]. As the level of international health financing stabilizes, high-HIV prevalence countries must increase HIV funding from domestic budgets [5], and continue to demonstrate the value for money of their AIDS response strategy to secure sustained donor funding [6,7]. Against this background of changing global health funding and priorities, HIV programs need to monitor and maintain the 5.2 million people currently on therapy, expand treatment initiations to people in earlier stages of infection according to WHO's 2010 guidance [8], and transition to less toxic but more expensive (tenofovir-based) antiretroviral regimens that may be more effective for chronic treatment [9]. Clear evidence on what works is vital for prioritizing program activities and budget allocations. The study by Phillips and colleagues [10] is timely to address the important question of the role of viral load monitoring in preventing the spread of antiretroviral drug resistance. Against the hypothesis that delaying the roll-out of viral load monitoring would result in a worldwide escalation of viral resistance, their modeling suggests that postponing the introduction of routine viral load monitoring will have limited consequences for resistance transmission: 12.4% of new HIV infections are predicted to have primary antiretroviral resistance in 2020 if clinical monitoring is used throughout, compared with 5.4 and 6.1% if viral load-guided switching were introduced in 2010 or 2015, respectively. Phillips and colleagues' findings strengthen the policy consensus and WHO recommendation ā so far based on individual patient outcomes and cost-effectiveness in the shorter term [11,12] ā that resource-poor countries need not delay ART roll-out because of limitations in laboratory capacity [13]. This is good news, especially for the next few years when HIV programs in many low-income settings are forced to ration new treatment initiations [14], and other ART-supportive activities such as patient adherence support remain underfunded [15]. In high HIV prevalence African countries where a viral load test costs $45ā80 and overall delivery of first-line ART $600 per patient-year [12,16,17], omitting viral load monitoring (at one or two tests per year) would allow 8ā27% more patients to initiate first-line therapy. In addition, routine viral load testing is associated with an average 40% increased rate of early switching to ā more expensive ā second-line regimens [18]. In the Phillips' model, introduction of viral load monitoring increased the proportion of patients on second-line regimens by four-fold after 10 years [10]. While improving health outcomes by a small extent [11,12], viral load testing might therefore indirectly increase the average cost per patient by 20ā40% or more [19]. Reports by National AIDS programs to the WHO and UNAIDS show large variations in patient monitoring strategies, in rates of switching to second-line regimens, as well as in expenditures per patient [1,2,20]. Several middle-income countries such as Brazil use 3-monthly CD4 and viral load monitoring and a large number of first-line and second-line regimens. Low-income country Malawi, in contrast, implements the WHO-recommended Public Health approach [13], relying on clinical patient monitoring alone and providing a minimum set of WHO-recommended antiretroviral regimens [17]. The marked reductions in AIDS deaths documented in Malawi within years of its ART roll-out since 2004 [20,21] illustrate what can be achieved under a highly simplified medicinal and patient monitoring approach. Delaying the introduction of routine viral load monitoring is in keeping with UNAIDS' Treatment 2.0 strategy [22], an extension on WHO's Public Health approach that aims to further simplify delivery and improve effectiveness of ART. An improved profile of antiretroviral regimens (one pill a day containing a regimen that is forgiving of suboptimal adherence and nontoxic, thus minimizing the need for laboratory monitoring) should allow decentralized community-based treatment delivery. The strategy also promotes an enhanced focus on HIV testing, and on linking treatment delivery with behavioral change communication, to maximize prevention effects. Whereas the antiretroviral regimens envisaged for Treatment 2.0 remain to be developed, ongoing evaluation of the program performance and health impact of public health ART approaches such as in Malawi and Uganda [23] should critically inform global policies. In 2011, Malawi will adopt the WHO recommendation to initiate ART at a CD4 threshold of 350 cells/Ī¼l, and transition to tenofovir-based first-line regimens ā while for the moment maintaining its practice of minimum patient laboratory monitoring [17]. As patients accumulate years on ART, notably when started at higher CD4 cell counts, longer-term health outcomes and viral resistance surveillance [2,24] will also prove or disprove model predictions ā which remain a main guidance at the moment. In the long term, ART programs should aim to expand routine viral load monitoring to prevent viral resistance and preserve the effectiveness of antiretroviral regimens. This will become more affordable and more cost-effective as prices of viral load tests and of second-line antiretroviral drugs continue to decrease. In the short term, while high-prevalence countries continue prioritizing the roll-out of HIV testing and counseling and ART initiations, supportive interventions could focus on effective antiretroviral procurement and distribution to minimize health system-induced treatment interruptions, and on patient adherence support to improve retention and survival on first-line regimens [2,24ā26].